Functional geometry of the cortex encodes dimensions of consciousness

Consciousness is a multidimensional phenomenon, but key dimensions such as awareness and wakefulness have been described conceptually rather than neurobiologically. We hypothesize that dimensions of consciousness are encoded in multiple neurofunctional dimensions of the brain. We analyze cortical gradients, which are continua of the brain’s overarching functional geometry, to characterize these neurofunctional dimensions. We demonstrate that disruptions of human consciousness – due to pharmacological, neuropathological, or psychiatric causes – are associated with a degradation of one or more of the major cortical gradients depending on the state. Network-specific reconfigurations within the multidimensional cortical gradient space are associated with behavioral unresponsiveness of various etiologies, and these spatial reconfigurations correlate with a temporal disruption of structured transitions of dynamic brain states. In this work, we therefore provide a unifying neurofunctional framework for multiple dimensions of human consciousness in both health and disease.


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We require information from authors about some types of materials, experimental systems and methods used in many studies. Here, indicate whether each material, system or method listed is relevant to your study. If you are not sure if a list item applies to your research, read the appropriate section before selecting a response. Methods n/a Involved in the study ChIP-seq Flow cytometry

MRI-based neuroimaging
For an fMRI study of cognitive function, Desmond and Glover (referecne 69) reported that about 25 subjects are necessary to achieve 80% power for a 0.5% increase of activity. We also conducted power analysis based on our previous study with graded sedation of propofol (referecne 70). The average Cohen's d as a measure of the effect size was 0.56. For 80% power and !=0.05, n=24 human subjects will be needed. The obtained subjects in Dataset-1 (n=26) and Dataset-2 (n=23) are above or very close to the suggested optimal group size for reliable statistics in functional MRI studies. The number of subjects in  and 7) are limited. However, we evaluated the specificity of our results in an independent cohort of 248 subjects consisting of healthy control participants and patients with psychiatric disorders (schizophrenia, bipolar disorder and attention deficit/hyperactive disorder).
No data were excluded in Dataset-1 or Dataset-3. Dataset-2 originally had 26 subjects. Among them, three subjects had to be excluded from further data analysis because of excessive movements, resulting in 23 subjects. In Dataset-4, 6 out of 13 patients diagnosed as unresponsiveness wakefulness syndrome (UWS) had to be excluded due to cortical distortions, resulting missing values in at least one of 400 cortical areas from the pre-defined brain parcellation scheme. In Dataset-5, the original dataset included 272 subjects encompassing healthy individuals (n=130) and individuals with psychiatric disorders including schizophrenia (SCHZ, n=50), bipolar disorder (BD, n=49), and attention deficit/hyperactivity disorder (ADHD, n=43). Twenty-four subjects were excluded due to lack of T1 images or resting-state data, or the overall head motion range were above 3 mm, or the data had insufficient degree of freedom after band-pass filtering and motion scrubbing. This resulted in 116, 44, 49, and 39 for healthy controls, SCHZ, BD and ADHD in our analysis (248 in total). The exclusion criteria were preestablished.
One of the key findings, i.e., a degradation of Gradient-1 induced by propofol anesthetics, was first found in Dataset-1 and reproduced independently in Dataset-2.
The experiments were not randomized because within-subject design was used in Dataset-1, Dataset-2, and Dataset-3. Dataset-4 and Dataset-5 were collected from independent research sites with different research protocols.
The investigators were not blinded to allocation during experiments and outcome assessment.

Human research participants
Policy information about studies involving human research participants Population characteristics

Recruitment
Ethics oversight Note that full information on the approval of the study protocol must also be provided in the manuscript.

Magnetic resonance imaging
Experimental design Design type Design specifications Dataset-1 included 26 healthy participants (right-handed; male/female: 13/13; age: 19-34 years). All participants were classified as American Society of Anesthesiologists (ASA) physical status I. Dataset-2 included 26 participants (right-handed; male/female: 12/14; age: 27-64 years). They were undergoing an elective trans-sphenoidal approach for pituitary microadenoma resection. The pituitary microadenomas were diagnosed by their size (<10 mm in diameter without growing out of the sellar region) based on radiological examinations and plasma endocrinal parameters. The participants were classified as ASA physical status I or II. Dataset-3 included 12 participants (right-handed; male/female: 7/5; age: 32-66 years). They were undergoing an elective trans-sphenoidal approach for pituitary microadenoma resection, and were classified as ASA physical status I or II. Dataset-4 included 16 healthy controls (male/female: 8/8; age: 23-65 years) and 21 patients (male/ female: 18/3; age: 8-78 years) with disorders of consciousness. The patients were assessed using the Coma Recovery Scale-Revised (CRS-R) on the day of fMRI scanning. Of those assessed, 13 patients were diagnosed as unresponsiveness wakefulness syndrome, and 8 were diagnosed as minimally conscious state. The detailed information of Dataset-5 (psychiatric cohort) can be found in a published study by Poldrack et al., 2016, Scientific Data.
Dataset 1: Healthy participants were recruited by listing on UMClinicalStudies.org and by postings at area colleges and community groups in Ann Arbor. Interested volunteers called the phone number of a designated recruiter for an initial phone screening. The initial phone screening consisted of questionnaires related to medical history, demographic information, handedness, inclusion and exclusion criteria and procedure standard MRI screening questionnaire. The participants completed the questionnaires, which were reviewed by the study team. The health status was confirmed by the attending anesthesiologist before the study on site. After the eligibility was confirmed by the study team, the one-time research study session was scheduled. None of the participants had psychiatric or neurological disorders (or a history thereof) in the study.
Dataset-2, Dataset-3 and Dataset-4: The online recruitment system at Huashan Hospital helped to recruit all healthy participants and patients. For Dataset-2 and Dataset-3, the participants were screened using a study-specific screening form contain medical history and demographic information. They were classified as American Society of Anesthesiologists physical status I or II, with no history of craniotomy, cerebral neuropathy, vital organ dysfunction or administration of neuropsychiatric drugs. They had no contraindication for an MRI examination, such as vascular clips or metallic implants. For Dataset-4, the patients with disorders of consciousness were selected as a convenience sample. For each patient, clinical examination was repeatedly performed using standardized CRS-R assessments. None of the healthy controls had a history of neurological or psychiatric disorders, nor were they taking any kind of medication.
Dataset-5: Healthy adults were recruited by community advertisements from the Los Angeles area. Participants with adult ADHD, bipolar disorder, and schizophrenia were recruited using a patient-oriented strategy involving outreach to local clinics and online portals (separate from the methods used to recruit healthy volunteers). More detailed information of recruitment can be found in a published study by Poldrack et al., 2016, Scientific Data. For all datasets, informed consent was obtained from all participants (or patients' legal representatives in Dataset-4), and they were compensated for participation after the experiment.
We do not expect any resulting potential self-selection bias.
University of Michigan Institutional Review Board, Institutional Review Board of Huashan Hospital at Fudan University, and Institutional Review Boards at UCLA and the Los Angeles County Department of Mental Health.

Resting state and task design (event-related).
Dataset-1: Four task fMRI runs were conducted including 15-min wakeful baseline, during (30-min) and after (30-min) propofol infusion, and another 15-min recovery baseline. Behavioral responsiveness was assessed by hand-squeezing a rubber ball, which defined the periods of propofol deep sedation (i.e., loss of behavioral responsiveness). Behavioral responses were measured in mmHg of air pressure using BIOPAC (https://www.biopac.com) MP160 system with AcqKnowledge software (V5.0). Verbal instructions were programmed using E-Prime 3.0 (Psychology Software Tools, Pittsburgh, PA) and delivered via an MRI-compatible audiovisual stimulus presentation system. More details about experimental design can be found in our previous publication (reference 61). Dataset-2: Three 8-min resting-state fMRI scans were conducted including wakeful baseline, propofol light sedation, and propofol general anesthesia. Dataset-3: For the entire experiment, fMRI scanning continued for about one hour, ranging between 44 minutes and 62 minutes. A 10-min conscious baseline was first acquired, except for two participants in which baseline condition was for 6 and 11 minutes. After that, 0.05mg/kg/min of ketamine was infused for 10 minutes (0.5mg/kg in total), followed by 0.1 mg/kg/min for another 10 minutes (1.0mg/kg in total; except for two participants who received 0.1mg/kg/min infusion for 10 minutes). Afterwards, the infusion of ketamine was discontinued, and participants spontaneously regained responsiveness. Behavioral responsiveness was assessed during the fMRI scan. The verbal instruction "press the button" was programmed to play every 30 seconds using E-Prime 2.0 (Psychology Software Tools, Pittsburgh, PA) and delivered via an MRI-compatible audiovisual stimulus presentation system. Participants were instructed to press a

Statistical modeling & inference
Model type and settings button with their right index finger. The period of loss of behavioral responsiveness, defined as ketamine anesthesia, was determined by comparing the timing of verbal instruction and actual responsiveness during and after ketamine infusion. The fMRI data length of ketamine anesthesia was 18.2±7.6 minutes across participants. Dataset-4: The resting state fMRI scan lasted 400 seconds. Dataset-5: The resting state fMRI scan lasted 304 seconds. More detailed information can be found in Poldrack et al. 2016, Scientific Data.
Dataset-1: Behavioral responses were measured in mmHg of air pressure during squeezing the rubber ball, using BIOPAC (https://www.biopac.com) MP160 system with AcqKnowledge software (V5.0). By comparing the timing of ''action'' instructions and the actual motor response during and after propofol infusion, the periods during which a subject retained responsiveness (PreLOR), loss of responsiveness (LOR), and recovery of responsiveness (ROR) were determined. The offset of PreLOR, onset of LOR, offset of LOR, and onset of ROR were defined as the times of the last successful response of squeezing, the first failure to squeeze, the last failure to squeeze, and the first successful response of squeezing after LOR, respectively. Dataset-2: Behavioral responsiveness was assessed by the Ramsay scale (Ramsay et al., 1974). A participant was considered fully conscious (Ramsay 1-2) if they responded clearly and strongly to a verbal command ("strongly squeeze my hand!"), or considered mildly sedated if the response was clear but slow (Ramsay 3-4), or considered deeply sedated or anesthetized if there was no response (Ramsay 5-6). The Ramsay scale verbal command was repeated twice for each assessment. Dataset-3: Behavioral responsiveness was assessed during the fMRI scan. The verbal instruction "press the button" was programmed to play every 30 seconds using E-Prime 2.0 (Psychology Software Tools, Pittsburgh, PA) and delivered via an MRI-compatible audiovisual stimulus presentation system. Participants were instructed to press a button with their right index finger. The period of loss of behavioral responsiveness, defined as ketamine anesthesia, was determined by comparing the timing of verbal instruction and actual responsiveness during and after ketamine infusion.
Using AFNI's function 3dTproject, the time-censored data were band-pass filtered to 0.01 -0.1 Hz. At the same time, various undesired components (e.g., physiological estimates, motion parameters) were removed via linear regression. The undesired components included linear and nonlinear drift, time series of head motion and its temporal derivative, and mean time series from the white matter and cerebrospinal fluid.
Frame-wise displacement (FD) of head motion was calculated using frame-wise Euclidean Norm (square root of the sum squares) of the six-dimension motion derivatives. A frame and its each previous frame were excluded if the given frame's derivative value has a Euclidean Norm above FD=0.4 mm.
Based on a well-established brain parcellation scheme (reference 26), the fMRI time courses were extracted from 400 pre-